The immune system protects the body from external and internal pathogens, such as bacteria, fungi, viruses, and cancer cells. T lymphocytes, B-lymphocytes (antibody producers), NK/LAK cells and macrophages (monocytes) are all components of the immune system.
T lymphocytes regulate the "cell mediated immunity" and function as helper cells, killer cells, or suppressor cells. Helper cells cooperate with B-lymphocytes for antibody production or for generating other T cell responses. Killer T cells eliminate virus-infected cells and cancer cells or reject foreign grafts. Suppressor T cells serve to modulate responses of other T cell classes.
T lymphocytes function as cells or through the release of soluble factors known as lymphokines or interleukins. In recent years, these functionally and biochemically unique soluble proteins have been discovered to play a central role in regulating the responsiveness of the immune system and/or act as antigen-non-specific effector molecules capable of mediating one or more aspects of immune function.
Cell interactions involved in cell mediated immunity require soluble helper or suppressor proteins. Most of these proteins are synthesized by hemopoietic cells, especially lymphoid cells and monocytes.
Lymphokines (interleukins) are mediators of these biological responses and regulate or affect both immune responses and other physiological systems. Biological characterization of lymphokines is still in a preliminary stage. This is primarily due to the small amount of lymphokines produced in in vitro systems. Lymphokines are active at extremely low physiologic concentrations.
IL-2 is one well-studied T lymphocyte and NK/LAK cell regulatory factor. Conditioned media from lectin-stimulated mononuclear cells was found to contain a mitogenic factor that supports the continuous exponential growth of lectin-activated human T cells and subsequently NK/LAK cells. It is now clear that IL-2 provides a mitogenic stimulus after lectin- or antigen-initiated T-cell activation or for NK or LAK cell activation. Since the discovery of IL-2, other T cell and NK cell activating lymphokines, such as IL-4, IL-6, and IL-12 have been identified. It is reasonable to postulate that there are other T and NK/LAK cell lymphocyte regulating lymphokines.
In other unrelated work, there has been considerable research with respect to a group of proteins known as interferons. See generally, Borden, E. C., "Interferons--Expanding therapeutic roles (Editorial)", New Engl. J. Med. 326:(22)1491-1493, 1992; Borden, E. C. "Interferons" in Cancer Medicine, Holland, J. F., et al. (Eds.), Lea & Febiger, pp 927-936, 1993; E. Borden, Cancer 54:2770-2776 (1984); E. Borden, Interferons And Cancer: How The Promise Is Being Kept, "Interferons", Vol. 5, Acad. Press, 43-83 (1984). The interferons are a family of proteins, each with distinct properties. For example, interferon .alpha.2 is most effective in treating cancers and interferon .beta. is more effective for multiple sclerosis. Interferon .gamma. has a role in immune regulation.
As a result of a large body of research on the interferons, it has become clear that they induce the synthesis of many new proteins within cells they contact. It is also believed that some of the many proteins induced by the interferons must somehow mediate the interferon-induced biological effects. However, the induced proteins' role in mediating the effects of interferons is not fully understood. See E. De Maeyer, et al., "Interferons And Other Regulatory Cytokines", John Wiley And Sons (1988).
One interferon-induced protein of about 15,000 daltons (157 amino acids) was isolated from the cytoplasm of a line of human lymphoblastoid cells after induction by interferons. In addition to the purification to homogeneity, the cloning and sequencing of the DNA and the amino acid sequence deduced from the cDNA have been reported. Particular portions of the gene responsible for transcription and the mechanism that hosts use to modify a 17-kDa precursor (about 165 amino acids) of the protein have also been defined. The 17-kDa protein differs from the secreted 15-kDa protein in that the 17-kDa protein has eight additional amino acids at the carboxy terminus. (The amino acid sequence of the 17-kDa protein, is disclosed below at SEQ ID NO:1.) See B. Korant, et al., J. Bio. Chem. 259:14835-14839 (1984); D. Blomstrom, et al., J. Bio. Chem. 261:8811-8816 (1986); N. Reich, et al., P.N.A.S. USA 84:6394-6398 (1987); E. Knight, et al., J. Bio. Chem. 263:4520-4522 (1988); N. Feltham, et al. J. Interf. Res. 9:493, 506 (1989).
We refer below to the 15-kDa protein as IL-16. (The 15-kDa secreted protein is referred to as DA15 and the 17-kDa precursor is referred to as DA17 in U.S. Ser. Nos.: 07/998,896, 07/590,565 and 07/486,473. The protein is referred to as "IL-15" in U.S. Ser. No: 08/086,529.)